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Bob Michell, DSc, MRCVS, is professor of
applied physiology and comparative medicine at the University of
London.
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Diarrhoea not only causes dehydration, it fundamentally results from
a fluid and electrolyte disturbance, hence oral rehydration therapy is
not simply symptomatic treatment but a remedy which engages the underlying
problem. In view of the
implementation of the Competition Commission’s findings on veterinary
dispensing, oral rehydration therapy may well become an area in which
pharmacists find themselves advising farmers, as well as adventurous
tourists.
Frequently the assumption of human medicine is that man was created as
a unique species and that animals are only relevant in so far as genetic,
surgical or pharmacological interventions can force them to imitate patterns
of human disease. Veterinary medicine instinctively adopts a different
outlook. Mammals are characterised both by the mechanisms that they share
and by the minority of mechanisms which make each species unique: comparative
medicine therefore rests on the similarities, which make a model relevant,
and the differences, which may be extremely informative. There should
always be caution, therefore, in applying data from one species to another,
but automatically to dismiss their relevance on the reflex assumption
of species differences is a barrier to innovation.
The World Health Organization identified oral rehydration as the greatest
life-saving advance of the 20th century. If the criterion had been cost-effectiveness
it would have been even further in front of the field. Once, cholera
was almost invariably lethal without access to intravenous rehydration,
now it is almost trivial provided there is prompt access to an appropriate
oral rehydration solution (ORS) and clean water in which to mix the powder.
During the past 10 years, oral rehydration therapy has seen a rapid growth
in the available therapeutic choices; paradoxically, this progress has
been far more advanced in veterinary medicine, where calves provide the
prime commercial market, than in human medicine.
The challenge is to base therapeutic choices on informed clinical advice
and increasingly on data-based confidence, not the guiles of marketing.
Thus in veterinary medicine, sadly, product choice still often reflects
brand allegiance or price rather than insight into likely effectiveness.
Yet there are sound principles from which clinicians may reasonably predict
likely efficacy. They rest on a clear picture of the problems we need
to solve; what precisely is diarrhoea and what are our therapeutic targets?
Although the treatment of diarrhoea in calves provides the focus, oral
rehydration therapy has applications in all species. These applications
are not restricted to diarrhoea, but it provided the original rationale
and the reason for WHO to single it out as the most important life-saving
medical advance of the 20th century. Although we should not naively assume
that principles validated in calves will apply to children, we should
not turn a blind eye on the grounds of assumed species differences. Calves
are not yet ruminants, unlike cattle. Like humans, they are functionally
simple-stomached animals until they are weaned on to solid food well
beyond the age at which most oral rehydration therapy is needed. Moreover
they offer the advantage for research in that they provide their own
experimental species, ie, it is possible to create diarrhoea in laboratory
calves and measure directly the parameters that influence survival, eg,
hypovolaemia, acidosis and prerenal failure. In children, most observations
are necessarily restricted to indirect and potentially misleading criteria,
such as changes in faecal output or need for supplementary fluids.
How does oral rehydration work?
Types of oral rehydration
solutions
There are three types of ORS:
· Type 1 — “WHO type”
· Type 2 — As type 1 but with nutrient
· Type 3 — As type 2 but with glutamine
Note: for further details see ‘Veterinary Formulary’,
6th edition. London, Pharmaceutical Press, due to be published
in 2005. |
Onset of diarrhoea indicates that net enteric uptake of sodium and
water, for whatever reason, is impeded to a degree which overwhelms the
substantial
compensatory capacity of the colon. Diarrhoea is the enteric form
of diuresis; a supranormal fluid loss resulting from reduced absorption.
Providing more fluid makes sense but only if it is absorbed and only
if it corrects the consequences of the losses. Trigger factors include
sudden nutritional changes and micro-organisms, but these provide
the
switch not the fundamental mechanism.
The most damaging effect of diarrhoea is to contract extracellular
fluid (ECF) volume, particularly plasma volume, together with metabolic
acidosis.
The latter results from bicarbonate loss in diarrhoeic faeces, tissue
ischaemia and anaerobic metabolism, compromised renal function, enteric
fermentation and, perhaps, excess chloride delivery promoting increased
colonic loss of bicarbonate. It is often severe, it does not parallel
dehydration in its intensity and it may cause dangerous hyperkalaemia,
despite the underlying tendency of faecal potassium loss and reduced
oral intake to produce cell potassium depletion and hypokalaemia. Additional
potassium loss in urine and faeces is the price of aldosterone-driven
sodium conservation in response to hypovolaemia.
Hyponatraemia, rather than hypernatraemia, is the usual outcome of
calf diarrhoea and reflects renal water retention, under the influence
of
antidiuretic hormone (ADH), in response to hypovolaemia. When plasma
volume is normal, ADH secretion, like thirst, is mainly driven by the
requirement for protection of the normal plasma sodium concentration.
Thus hyponatraemia and hypernatraemia indicate primary disturbances
of water balance rather than sodium balance.
Although hyponatraemia is likely to be asymptomatic until the fall
exceeds 15 mmol/L, it has another implication. Sodium is the osmotic
skeleton
of ECF, enabling it to resist the osmotic pull of the intracellular
solutes and dictating ECF volume. The immediate effect of gain or loss
of sodium
is not a change in plasma concentration but in ECF volume. When plasma
sodium falls, however, water is yielded to intracellular fluid causing
additional loss of ECF volume on top of external losses. The reason
for the fall is that once hypovolaemia is sufficiently severe, its
correction
temporarily supersedes the defence of plasma sodium concentration as
the primary target of the regulation of water balance, ie, ADH secretion
and water intake (in animals able to drink) both increase and plasma
sodium is diluted.
It follows from these principles, and from data in calves, that the
key properties of an ORS are:
· It should be efficiently absorbed
· It should restore ECF volume (and correct hyponatraemia)
· It should correct acidosis (and thereby reduce hyperkalaemia)
It may also be desirable to replace potassium deficits and, perhaps,
losses of calcium and magnesium.
What should an ORS contain?
The original principle underlying the WHO solution, which transformed
the treatment of cholera, was an isotonic solution with a 1:1 sodium:glucose
ratio, ie, glucose 2 per cent (100 mmol/L), Na+ 0.67 per cent (100
mmol/L) and anions (100 mmol/L).
A bicarbonate precursor (eg, citrate) to repair the acidosis is essential
and calves receiving an ORS without it may become rehydrated but severely
acidotic.
The optimum sodium:glucose ratio probably differs between species and
between healthy and diarrhoeic animals. But it is an inescapable obligation
to provide 145mmol of sodium for every litre of extracellular fluid needing
to be replaced. Thus the further below 90mmol/L we venture, the less
likely an ORS is to replenish ECF, including plasma volume. In designing
ORSs there can be conflict between data concerning sodium absorption
or water absorption; in my view, the optimum for sodium is the over-riding
consideration. Water absorbed without sufficient osmotic skeleton (sodium)
will not stay where it is needed in ECF. Instead, it will diffuse futilely
into cells.
The ability to correct dehydration, hypovolaemia and acidosis, are the
attributes of a classic type 1 ORS but subsequently other objectives
have become attainable. A type 2 solution has the properties expected
of type 1 solutions, but avoids the energy deficits imposed by their
low (2 per cent) glucose content; optimal for sodium absorption but inadequate
for metabolism. The most advanced type 3 solution adds to the attributes
of a type 2 solution the ability to sustain villus structure and enterocyte
function using glutamine. Unlike other amino acids, eg, glycine, which
merely give a further boost to sodium uptake, glutamine has unique importance
for both enteric and renal function, sustaining both enterocyte function
and villus architecture. Data from diarrhoeic calves demonstrate the
reality of its theoretical benefits. The traditional low glucose content
of an ORS is directed towards absorption; the energy content of three
litres of milk could only be provided by over 30 litres of ORS per day,
whereas the usual daily dose for calves is four litres. Unlike type 1
solutions, nutrient ORSs (type 2 or 3) need not be restricted to 48 hours’ use
at full strength because of their higher energy yield.
The optimum glucose content is linked to sodium content; some paediatricians
have feared, wrongly, that cholera type ORSs had too much sodium for
milder diarrhoeas and might cause hypernatraemia. Hypernatraemia caused
by oral rehydration therapy in children, however, has generally resulted
from osmotic diuresis, eg, associated with excess glycine, or, most usually,
with incorrectly prepared ORSs. Thus, by making the solution hypertonic
and drawing water into the intestine, the solutions lead to loss of water
from both cells and ECF, and hence to hypernatraemia. Nevertheless, if
glucose is absorbed, water travels with it, rather than being drawn into
the intestine. In diarrhoeic gut there are always likely to be unabsorbed
sodium ions available for absorptive co-transport with glucose. At least
in calves, nutrient ORSs do not cause hypernatraemia. These and other
less important aspects of ORS composition, eg, presence of glycine, are
fully reviewed.1
It is worth considering whether the ideal formulation depends on the
type of diarrhoea. In humans, success depends on the formulation more
than the type of diarrhoea, probably because even severe diarrhoea leaves
sufficient intestinal surface area unaffected and able, therefore, to
respond normally to an ORS of appropriate composition. It is important
to emphasise, in Ludan’s words, that the key to “management
of acute diarrhoea is simply to stop the dehydration rather than the
diarrhoea”. Sometimes diarrhoea may worsen transiently even though
the patient is improving. Provided that rehydration is successful, it
does not matter if some additional fluid “overspills” into
faeces pending the final cessation of the diarrhoea. Faecal output is
a fallible index of efficacy. This has long been understood in human
medicine and recently confirmed in calves. Unfortunately, changes in
faecal output feature prominently in the evaluation of human ORSs.
In the future, we may see a broader range of primary applications for
oral rehydration therapy, notably in exertional dehydration, eg, in humans
and horses, and in reducing the amount of parenteral fluids required
in conditions such as severe hypovolaemia or shock. What about antibiotics?
Granted that the front-line treatment of diarrhoea is with oral fluids,
the most pressing question is the additional role, if any, of antibiotics.
In human diarrhoea, the role for antibiotics has been progressively
reduced with few exceptions other than treatment of systemic effects.
We do not know whether similar trends are valid for veterinary medicine
in view of differences in epidemiology, management and nutrition,
let alone species. Yet antibiotics should only be used where essential,
in order to minimise emergence of resistance. So the relative efficacy
of antibiotics and oral rehydration, alone or in combination, is
a
key question demanding urgent answers yet receiving none. Why? First,
the answers may be commercially uncomfortable. Secondly, fashionable
funding of farm animal research has kept its gaze fixedly on intellectual
challenge to the detriment of urgent and attainable clinical priorities.
The role of antibiotics or oral fluids in combating diarrhoea seems
mundane, lacking the excitement of cloning genes for virulence factors
or engineering subunit vaccines. But the elimination of one pathogen
causing diarrhoea merely opens a niche for another. It is the classic
outcome of simplistic approaches to environmental problems, whether
in the gut or the countryside. Balances are complex and crude interventions
inadvertently cause new disturbances. Vaccines are likely to change
the causes of diarrhoea but ultimately they are unlikely to prevent
it. Market pressures and clinical choice
Clinical criteria have long served to assess dehydration and
rehydration despite their notorious fallibility; they offer no
sound basis for
comparing the efficacy of ORSs. Even loss of body weight (normally
a guesstimate since initial weight is usually unknown) when precisely
quantified remains a fallible guide, not least because fluid accumulated
in the intestine (“tomorrow’s diarrhoea”) dehydrates
the patient, ie, compromises its circulatory and extracellular fluid
volume but does not yet reduce its body weight. Nevertheless, there
are clear differences between ORSs in correcting the changes that are
likely to govern survival and recovery, many of them predictable from
composition.
In veterinary medicine, the choice lies with clients, mostly farmers,
and their clinical advisors. Companies should focus on the real and specific
strengths of their product, not on mythical attributes or promotional
incentives. It is said that farmers’ preference rather than veterinary
advice often dictates the choice. If health workers in Asia can persuade
mothers with no medical knowledge (and frequently great scepticism) to
accept advice on oral rehydration therapy, it should be easier for veterinarians
or pharmacists with educated clients to do the same. Those who have a
privileged position as providers of veterinary care must sustain it through
their ability to make informed clinical choices based on sound theory
and convincing evidence.
In human medicine, it would seem perverse if the demonstrated effectiveness
of glutamine in sustaining renal function and villus structure and function
were ignored. The potential benefits go beyond acute diarrhoea and include
all conditions where reduced food intake imperils villus architecture.
So far, the limited human studies have been discouraging, probably because
glutamine was added to traditional World Health Organization ORSs instead
of nutrient ORSs. The possible benefits of type 3 ORSs in human medicine
deserve careful and specific research, particularly when anything that
minimises the need for recourse to antibiotics is so important. Maybe
species differences are a real barrier, but maybe not; human patients,
especially children, deserve the benefit of the doubt. Reference
1. Michell AR. Oral rehydration for diarrhoea. Journal
of Comparative Pathology 1998;118:175–93. |
The
Pharmaceutical Journal